US3625946A - 1,4 endomethylene cyclohexane-2,3 endo-cio di carboximido glutarimides - Google Patents

1,4 endomethylene cyclohexane-2,3 endo-cio di carboximido glutarimides Download PDF

Info

Publication number
US3625946A
US3625946A US683091A US3625946DA US3625946A US 3625946 A US3625946 A US 3625946A US 683091 A US683091 A US 683091A US 3625946D A US3625946D A US 3625946DA US 3625946 A US3625946 A US 3625946A
Authority
US
United States
Prior art keywords
percent
cis
grams
endo
melting point
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US683091A
Other languages
English (en)
Inventor
Heinrich P Koch
Johannes Kotlan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F JOH KWIZDA
KWIZDA FA F JOHANN
Original Assignee
KWIZDA FA F JOHANN
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KWIZDA FA F JOHANN filed Critical KWIZDA FA F JOHANN
Application granted granted Critical
Publication of US3625946A publication Critical patent/US3625946A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the derivatives ac- ZG'OISMR 260/55'7R 55 424/2'67 cording to the invention are free of an aromatic phthalimide [51 1 [m m 5 31/32 grouping and exhibit a tranquilizing activity on certain parts of the central nervous y whereas are free f emb. 5 FM ryotoxic (teratogenous) secondary effects when administered to pregnant mammals.
  • Some known substituted succinimides and glutarimides which contain phthalimide groups in the alpha or beta position have a tranquilizing activity on certain portions of the central nervous system and differ from other conventional sedatives and hypnotics, such as barbituric acids, hydantoins, etc., in that the action is not accompanied by an initial excitation phase and there is a complete absence of narcotic or peripheral paralytic effects.
  • the novel compounds have an extremely low acute toxicity and basically differ also in this respect from other previously used drugs having the same indication. The therapeutical activity is obtained quickly after oral or parenteral administration and is maintained for a relatively long time.
  • the agents of the above-mentioned type particularly the compounds known as thalidomides, have a serious disadvantage residing in the embryotoxic (teratogenous) secondary effects, which occur after the administration to pregnant women and often result in serious malformations of the infant. in spite of their undeniable advantages as outlined above, the use of these agents has been entirely prohibited in numerous countries for the reasons given.
  • the present invention is based on the discovery that this undesired embryotoxic activity is due to a specific part of the structure, namely, the aromatic phthalimide structure.
  • a and B each represent a bivalent hydrocarbon radical, which may be saturated or unsaturated, in the simplest case a methylene, ethylene or vinylidene grouping, or a larger radical, which may have a linear, branched-chain, cyclic, bicyclic, aromatic or polynuclear configuration, B may also represent an oxygen atom or two hydrogen atoms, each of which is bound to the carbon atom bearing substituents X, and X,,; the hydrocarbon radicals represented by A and/or B may be substituted by halogen, alkyl, aryl, cycloalkyl, aralkyl, alkylidene or arylidene groups, X,X each represent hydrogen, halogen or alkyl group substituents, which may be substituted, particularly by oxygen or oxygen-containing radicals, X and X together may represent a double bond, Y represents an oxygen atom, or a nitrogen atom in which the third valence
  • B preferably represents two hydrogen atoms, a methylene or ethylene radical or an oxygen atom.
  • Further examples of B are phenylene, isopropylidene, diphenylethylene or substituted methylene radicals, such as CHr-HC and C120
  • substituents on the imide nitrogen are lower alkyl groups, e.g., methyl, ethyl, any of the various propyl, butyl or allyl groups etc.; cyclohexyl; aryl, aralkyl and alkaryl groups, e.g., phenyl, benzyl, p-toluyl, etc.
  • novel compounds can be produced by methods in which the corresponding cyclic or polycyclic dicarboxylic acids, which can easily be obtained as products of Diels-Alder reactions, or specific reactive functional derivatives thereof, particularly their anhydrides, chlorides or esters, are reacted with aminodicarboxylic acids, e.g., with alpha-aminosuccinic acid (aspartic acid) or alpha-aminoglutaric acid (glutamic acid) or suitable derivatives thereof, such as their esters, amides, diamides or imides.
  • aminodicarboxylic acids e.g., with alpha-aminosuccinic acid (aspartic acid) or alpha-aminoglutaric acid (glutamic acid) or suitable derivatives thereof, such as their esters, amides, diamides or imides.
  • the intermediate products obtained in reaction are transformed by treatment with a dehydrating; agent, such as acetic anhydride, acetyl chloride, POCl or the like, into the corresponding dicarboximidosuccinic or dicarboximidoglutaric anhydrides, e.g.,
  • anhydrides are reacted with ammonia, its salts, such as NH Cl or (NHQ CO or other Mi -yielding compounds, such as urea, thiourea, guanidine, guanidine salts, formamide, acetamide or the like, to form the cyclic imides:
  • the resulting products may be transformed in the usual manner into the saturated compounds. lf two or more double bonds capable of hydrogenation and of different reactivity are present, one or more of them may be selectively saturated (partial hydrogenation).
  • the cyclic imides of aminodicarboxylic acids rather than the free aminodicarboxylic acids may be used in the first reaction step so that the starting products are subjected to the transformation of the anhydride into an imide otherwise carried out in step 111.
  • Monoamides of aminodicarboxylic acids e.g., asparagine, glutamine, isoasparagine or isoglutamine, may be used instead of the free aminodicarboxylic acids to obtain the end products of step 111 in the second reaction step.
  • a cyclic or polycyclic dicarboxylic imide may be reacted with a suitable reactive derivative of succinic acid or glutaric acid, e.g., the reaction of the potassium salt of 1,4-endomethylene-A -cyclohexene-2,3-dicarboxy1ic imide with diethyl alpha-bromosuccinate results in the formation of diethyl l,4-endomethylene-A -cyclohexene-2,3-dicarboximidosuccinate.
  • This ester is transformed into the imide (according to ill) by reaction with NH followed by treatment with acetylchloride.
  • the Diels-Alder reaction to form the cyclic or polycyclic dicarboxylic component is carried out at the end of the sequence of reactions.
  • alpha-maleinimidoglutarimide reacts with conjugated dienes to form the corresponding cyclic or polycyclic dicarboximidoglutarimides.
  • the compounds prepared according to the invention may be used as therapeutics alone or in combination with other agents and adjuvants or as intermediates in the preparation of therapeutics. They may also be used as starting products of further syntheses.
  • EXAMPLE 1 Twenty grams of DL-aspartic acid and 23 grams of A- cyclohexenel,2-cis-dicarboxylic anhydride were boiled in 80 ml. of absolute pyridine to complete dissolution. The solvent was then removed in vacuo and the residue, together with 50 ml. of acetic anhydride was shortly heated to boiling. A- cyclohexene-1,Z-cis-dicarboximidosuccinic anhydride crystallized upon cooling. Melting point 192193 C. Yield 31.5 grams.
  • EXAMPLE 2 Twenty grams of DL-aspartic acid and 25 of grams 1,4-endomethylene-A -cyclohexene2,3-endo-cis-dicarboxylic anhydride were reacted in the procedure of example 1 to form the 1,4-endomethylene-A -cyclohexene-2,3-endo-cis-dicarboximidosuccinic anhydride, melting point l-17l C., yield 36.5 grams.
  • EXAMPLE 6 Forty-five grams of L-glutamic acid and 53 grams of 1,4- endo-methylene-N-cyclohexene-Z,3'endo-cis-dicarboxylic anhydride were boiled together with 150 ml. pyridine for 2 hours. After cooling, the mixture was filtered and evaporated in vacuo. The residue was boiled up with 100 ml. of acetic anhydride and reevaporated to one-half its volume. Part of the resulting 1,4-endmethylene-A -cyclohexene-2,3-endo-cisdicarboximidoglutaric anhydride crystallized upon cooling and was filtered off. An addition of ether to the mother liquor resulted in a quantitative precipitation. Melting point 1'75- 176 C.
  • EXAMPLE 7 32.5 grams of L-glutamic acid and 36 grams of 1,4-endo'methylene-A -cyclohexene-2,3-exo-cis-dicarboxylic anhydride, were reacted by the procedure of example 6 to form l,4-endomethylene-N-cyclohexeneQ,3-cisdicarbox imidoglutaric anhydride, melting point 2l4-216" C. quu lvo, (275.25): Calculated 5.09 percent N, found 5.06 percent N.
  • EXAMPLE 8 Forty-five grams of L-glutamic acid and 53 grams of 1,4-endomethylenecyclohexane-Z,3-endo-cis-dicarboxylic anhydride were reacted using the procedure of example 6 to form 1,4-endomethylenecyclohexane-Z,3endo-cis-dicarboximidoglutaric anhydride, melting point 2 l42 16 C.
  • EXAMPLE 9 41.5 grams of L-glutamic acid and 50 grams of 1,4-endoethylene-A -cyclohexene-Z,3-endo-cis-dicarboxylic anhydride were reacted using the procedure of example 6 to form l,4-endoethylene-N-cyclohexene-Z,3-endo-cis-dicarboximidoglutaric anhydride, melting point 246248 C.
  • the above anhydride was transformed into l,4-endoethylene-M-cyclohexene-2,3-endo-cis-dicarboximidoglutarimide, melting point 240-242 C.
  • EXAMPLE 10 29.5 grams of L glutamic acid and 35.6 grams of methyl- 1,4-endomethylene-A -cyclohexane-Z,3-cis-dicarboxylic anhydride (Diels-Alder adduct of maleic anhydride and methyl cyclopentadiene) were reacted by the procedure of example 1.
  • the product corresponding to methyl-1,4-endomethylene- N-cyclohexene-Zfi-cis-dicarboximidoglutaric anhydride was crystallized only with difficulty and was subjected to further processing without purification. Part of the product was crystallized out of a mixture of glacial acetic acid and acetic anhydride for analysis. Melting point 171-173 C.
  • EXAMPLE 11 18.3 grams of L-glutamic acid and 21 grams of 1,4-endoxocyclohexane-Z,3-exo-cis-dicarboxylic anhydride were boiled in 100 ml. of pyridine to complete dissolution. The pyridine was then largely removed in vacuo. The residue was received in dilute H SO and the solution was extracted with either to exhaustion. The residue obtained by the distillation of the ether was boiled up together with 40 ml. of acetic anhydride. l,4-endoxcyc1ohexane-2,3-exo-cis-dicarboximidoglutaric anhydride crystallized upon cooling. Melting point 219-220 C., yield 19.7 grams.
  • EXAMPLE 12 16.3 grams of L-glutamic acid and 41.2 grams of l,4,5,6,7,7-hexachloro-1 ,4-endomethylene-A -cyclohexene- 2,3-endo-cisdicarboxylic anhydride (Diels-Alder adduct of maleic anhydride and hexachlorocyclopentadiene) were reacted by the procedure of example 1 to form 1,4,5,5,6,7,7- hexachloro- 1 ,4-endomethylene-A -cyclohexene-2,3-endo-cisdicarboximidoglutaric anhydride, melting point 235240 C., yield about 25 grams.
  • EXAMPLE 13 29.5 grams of L-glutamic acid and 55.5 grams of 5,6; 7,8- dibenzo-bicyclo( 2,2,2 )octane-Z,3-cis-dicarboxylic anhydride (Diels-Alder adduct of maleic anhydride and anthracene) were reacted using procedure of example 1 to form 5,6; 7,8- dibenzo-bicyclo(2,2,2)octane-2,3-cis-dicarboximidoglutaric anhydride. Melting point 283-285 C. Yield 58 grams. C H NO (387.39): Calculated 3.62 percent N, found 3.69 percent N.
  • EXAMPLE 14 6.7 grams of L-glutamic acid and 15 grams of 7-diphenylmethylene-1,4-endomethylenecyclohexane-2,3-endo-cisdicarboxylic anhydride (partially hydrogenated Diels-Alder adduct of maleic anhydride and diphenylfulvene) were reacted using the procedure of example 1 to form 7-diphenylmethylenel ,4-endomethylenecyclohexane-2,3-endo-cisdicarboximidoglutaric anhydride, melting point 254-256 C.
  • EXAMPLE 15 Twenty grams of a freshly prepared potassium compound of 1.4-endomethyleneA cyclohexene-Z.3-endo-cis-dicarboxylic acid imide and 25 grams of diethyl alphabromosuccinate were heated together with ml. of dimethylformamide on a water bath for 1 hour. After cooling, the solvent was removed in vacuo. The residue was received in water and repeatedly shaken with ether. The combined ether extracts were dried over Na SO filtered and evaporated. The resulting diethyl a1pha-( l,4-endo-methylene-A -cyclohexene-2,3-endo-cisdicarboximido)-succinate was received in absolute ethanol without further purification.
  • EXAMPLE 16 Ten grams of L-alpha-aminosuccinic acid-gamma-amide (L-asparagine) and 12.5 grams of 1,4-endomethy1ene-A -2,3- endo-cis-dicarboxylic anhydride were boiled in 50 ml. of pyridine to complete dissolution. The pyridine was then largely removed in vacuo. Four hundred and thirty milliliters of acetyl chloride were added to the residue. The resulting mixture was heated on a water bath for 1 hour and was then evaporated.
  • L-alpha-aminosuccinic acid-gamma-amide L-asparagine
  • 1,4-endomethy1ene-A -2,3- endo-cis-dicarboxylic anhydride were boiled in 50 ml. of pyridine to complete dissolution. The pyridine was then largely removed in vacuo. Four hundred and thirty milliliters of acetyl chloride were added to
  • EXAMPLE 17 Ten grams of L-alpha-aminoglutaric acid-delta-amide (L- glutamine) and 11.5 grams of 1,4-endomethylene-A cyclohexene-Z,3-endo-cis-dicarboxylic anhydride were reacted using the procedure of example 16 to form 1,4-endomethylene-A -cyclohexene- 2,3-endo-cis-dicarboximidoglutarimide, melting point 235236 C.
  • EXAMPLE 18 Ten grams of DL-alpha-aminoglutarimide and 15 grams of l ,4-endomethylene-A -cyclohexene-2,3-endo-cis-dicarboxylic anhydride were boiled in 50 ml. of pyridine. The solution was filtered and evaporated in vacuo. The residue was shortly boiled with a little glacial acetic acid and acetic anhydride. 1,4-endomethylene-N-cyclohexene-Z,3-endo-cis-dicarboximidoglutarimide crystallized together with other products upon storage in a refrigerator and was obtained in a pure state by repeated recrystallization from aqueous dimethylformamide. Melting point 235 C. C H N O (274.27): Calculated 10.22 percent N, found 9.98 percent N.
  • EXAMPLE 19 27.5 grams of l,4endomethylene-A -cyclohexene-2,3- endo-cis-dicarboximidoglutaric anhydride obtained by the procedure of example 6 were finely ground with 77.5 grams of methylamine hydrochloride and heated to 180190 C. on an oil bath for 1 hour. The cooled mass was received in acetone. The surplus methylamine hydrochloride separated and was removed.
  • EXAMPLE 20 5.5 grams of N-methyl-alpha-(maleinimido)-glutarimide were dissolved in 40 milliliters of dimethylformamide and 5 grams of freshly distilled cyclopentadiene were added to the solution. When the latter had been stored for 24 hours, it was evaporated in vacuo to one-third of its original volume. After the addition of water and storage in a refrigerator, N-methylalpha-( l,4-endomethylene-N-cyclohexene-Z,3-endo-cisdicarboximido)-glutarimide was crystallized. Melting point C, H N O (288.30): Calculated 9.72 percent N, found 9.84 percent N.
  • EXAMPLE 21 27.5 grams of l,4-endomethylene-A -cyclohexene-2,3- endo-cis-dicarboximidoglutaric anhydride obtained by the procedure of example 6 were melted together with 10 grams of benzylamine. The cooled mass was dissolved in aqueous dimethylformamide whereby N-benzyl-alpha-( 1,4-endomethylene-AF-cyclohexene-2,3-endo-cis-dicarboximido)- glutarimide was crystallized. Melting point 137-138 C. C l-1 N (364.39): Calculated 7.71 percent N, found 7.75 percent N.
  • EXAMPLE 23 Twenty grams of l,4-endomethylen e-A -cyclohexene-2,3-- exo-cis-dicarboximidoglutaric anhydride produced by the procedure of example 7 were heated together with 10 grams of methylamine hydrochloride at 180-190 C. for 1 hour. The cooled mass was dissolved in a little dimethylformamide, diluted with water and extracted with ether. The ether extract was evaporated. The residue was dissolved in ethanol, from which N-methylalpha-( l,4-endomethylene-A -cyclohexene- 2,3-exo-cis-dicarboximido)-glutarimide was crystallized. Melting point 170172 C.
  • EXAMPLE 24 14.5 grams of l,4-endothylene-A -cyclohexene-2,3-endocis-dicarboximidoglutaric anhydride obtained by the procedure of example 9 were reacted with methylamine hydrochloride using the procedure of example 23. N-methylalpha-( 1,4-endoethylene-A -cyc1ohexene-Z,3-endo-cis-dicarboximido)-glutarimide, melting point ll 86 C. C H N Q, (303.54): Calculated 9.27 percent N, found 9.18 percent N.
  • EXAMPLE 25 The l.4endoxocyclohexane-2,3-exo-cis-dicarboximido-glutaric anhydride obtained by the procedure of example 1 l was reacted with methylamine hydrochloride by the procedure of example 23. N-methyl-alpha-(l,4-endoxocyclohexane-2,3- exo-cis-dicarboximido)-glutarimide, melting point 290-293 C.
  • EXAMPLE 26 Forty grams of DL-aspartic acid and 55 grams of 1,4endoethylene-A -cyclohexene-2,3-endo-cis-dicarboxylic anhydride were reacted using the procedure of example 1. Yield: 67 grams l,4-endoethylene-A -cyclohexene-2,3-endo-cis-dicarboximido-succinic anhydride, melting point 2 12-2 13 C. C, l-l, -,NO (275.25): Calculated 5.09 percent N, found 4.97 percent N.
  • the last-mentioned compound was hydrogenated to form 1 ,4-endoethylenecyclohexane-2,3-cis-dicarboximidosuccinimide, melting point 234235 C.
  • EXAMPLE 27 26.6 grams of DL-aspartic acid and 33 grams of 1,4-endomethylene-A -cyclohexene-2,3-exo-cis-dicarboxylic anhydride were reacted using the procedure of example 2 to form l,4-endomethylene-N-cyclohexene-Z,3-exo-cis-dicarboximidosuccinic anhydride, melting point l-l 96 C.
  • the above compound was hydrogenated to form 1,4-endomethylenecyclohexane-Z,3-exo-cis-dicarboximidosuccinimide, melting point 200-202 C.
  • EXAMPLE 28 Twenty-five grams of DL-aspartic acid and 31.5 grams of l,4-endoxocyclohexane-2,3-exo-cis-dicarboxylic anhydride were reacted by the procedure of example 1 to form 1,4-endoxocyclohexane-2,3-exo-cis-dicarboximidosuccinic anhydride. Yield 42 grams, melting point 216-218 C. C H NO (265.22): Calculated 5.28 percent N, found 5.12 percent N.
  • EXAMPLE 29 Ten grams of l,4-endoxomethylene-A -cyc1ohexane-2,3- endo-cis-dicarboximidosuccinic anhydride prepared by the procedure of example 2 were kept together with 5 grams of methylamine hydrochloride in a molten state at l70-l 80 C. for 1 hour. The cooled mass was washed with water and dissolved in aqueous alcohol, from which N-methyl-alpha-( 1,4- endomethylene-A-cyclohexene-2,3-endo-cis-dicarboximido)- succinimide was crystallized melting point 135-136 C. C H N O (274.27): Calculated 10.22 percent N, found 10.32 percent N.
  • EXAMPLE 30 1 ,4-endoethylene-A -cyclohexene-2,3-endo-cisdicarboximidosuccinic anhydride prepared by the procedure of example 26 was transformed into N-methy1-a1pha-(1,4-endoethylene-M-cyclohexene-2,3-endo-cis-dicarboximido)-suc cinimide by a procedure which is analogous to that of example 29. Melting point 188-l90 C.
  • EXAMPLE 32 Thirty grams of L-glutamic acid and 36 grams of 2-exomethyl-1,4-endomethylene-A -cyclohexene-2,3-endo-cisdicarboxylic anhydride (adduct of citraconic anhydride and cyclopentadiene) were reacted and process by the procedure of example 1 to form 2-exomethyl-l.4-endomethylene-A cyclohexene-2,3-endo-cis-dicarboximidoglutaric anhydride, melting point 204205 C.
  • a compound as claimed in claim 1 which is 1.4-endomethylene-cyclohexane-Z,3-endo-cis-dicarboximidoglutarimide.
  • a compound as claimed in claim 1 which is N-methylalpha-( l,4-endomethylene-cyclohexane-2,3-endo-cis-dicarboximido)-glutarimide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US683091A 1966-11-08 1967-11-02 1,4 endomethylene cyclohexane-2,3 endo-cio di carboximido glutarimides Expired - Lifetime US3625946A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AT1034166A AT278739B (de) 1966-11-08 1966-11-08 Verfahren zur Herstellung von neuen Anhydriden und Imiden substituierter Dicarbonsäuren

Publications (1)

Publication Number Publication Date
US3625946A true US3625946A (en) 1971-12-07

Family

ID=3621670

Family Applications (1)

Application Number Title Priority Date Filing Date
US683091A Expired - Lifetime US3625946A (en) 1966-11-08 1967-11-02 1,4 endomethylene cyclohexane-2,3 endo-cio di carboximido glutarimides

Country Status (6)

Country Link
US (1) US3625946A (de)
AT (1) AT278739B (de)
CH (2) CH530991A (de)
DE (1) DE1695346C3 (de)
FR (1) FR1570452A (de)
GB (1) GB1182709A (de)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4132799A (en) * 1975-05-09 1979-01-02 Merck & Co., Inc. N-(Benzoxazolinyl-2-one)-tricyclic dicarboximides
US5443824A (en) * 1994-03-14 1995-08-22 Piacquadio; Daniel J. Topical thalidomide compositions for surface or mucosal wounds, ulcerations, and lesions
US5593990A (en) * 1993-03-01 1997-01-14 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US6114355A (en) * 1993-03-01 2000-09-05 D'amato; Robert Methods and compositions for inhibition of angiogenesis
US6228879B1 (en) 1997-10-16 2001-05-08 The Children's Medical Center Methods and compositions for inhibition of angiogenesis
RU2174516C2 (ru) * 1993-07-02 2001-10-10 Селген Корпорейшн Имиды как ингибиторы tnf-альфа
US20030164219A1 (en) * 2002-02-20 2003-09-04 Joerg Brahm Headliner/duct assembly and welding process therefor
US20030191098A1 (en) * 1996-11-05 2003-10-09 D'amato Robert J. Methods and compositions for inhibition of angiogenesis
US6673828B1 (en) 1998-05-11 2004-01-06 Children's Medical Center Corporation Analogs of 2-Phthalimidinoglutaric acid
US7495089B2 (en) 1995-10-23 2009-02-24 The Children's Medical Center Corporation Therapeutic antiangiogenic endostatin compositions
US7812169B2 (en) 2000-11-30 2010-10-12 The Children's Medical Center Corporation Method of synthesis of 4-amino-thalidomide enantiomers
US8143283B1 (en) 1993-03-01 2012-03-27 The Children's Medical Center Corporation Methods for treating blood-born tumors with thalidomide

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4644066A (en) * 1968-09-18 1987-02-17 Raychem Corporation Flame retardants and compositions containing them
DE2460304C2 (de) * 1974-12-20 1983-08-04 Grünenthal GmbH, 5190 Stolberg 1-n-Propyl-4-phthalimido-piperidin-2,6-dion, Verfahren zu seiner Herstellung und dieses enthaltende Arzneimittel

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2231887A (en) * 1939-03-03 1941-02-18 Du Pont Chemical process
US2545283A (en) * 1945-10-10 1951-03-13 Du Pont Tertiary diacyl amine insecticides
US2830991A (en) * 1954-05-17 1958-04-15 Gruenenthal Chemie Products of the amino-piperidine-2-6-dione series
DE1093364B (de) * 1956-06-11 1960-11-24 Gruenenthal Chemie Verfahren zur Herstellung von Derivaten von Amino-piperidin-2,6-dionen
US3081308A (en) * 1959-12-29 1963-03-12 Searle & Co 5-carbocyclic-3-imidomethyloxazolidines and process
US3314953A (en) * 1964-03-16 1967-04-18 Richardson Merrell Inc 1-substituted-3-phthalimido-2, 5-dioxopyrrolidines
US3314969A (en) * 1963-07-30 1967-04-18 Chevron Res Process for the preparation of n-polyhaloethylthio compounds
US3436396A (en) * 1967-04-19 1969-04-01 Mcneilab Inc 1,4 and 1,5-bis(gamma-hydroxy-gamma,gamma-di-(2-pyridylmethyl)) - 5 - norbornene - 2,3 - dicarboximide and derivatives thereof
US3453271A (en) * 1967-05-02 1969-07-01 Mcneilab Inc Di-substituted 5-norbornene 2,3-dicarboximides
US3457272A (en) * 1964-03-03 1969-07-22 Wyeth John & Brother Ltd 4-(o-benzoylsulfimido)lower fatty amines

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2231887A (en) * 1939-03-03 1941-02-18 Du Pont Chemical process
US2545283A (en) * 1945-10-10 1951-03-13 Du Pont Tertiary diacyl amine insecticides
US2830991A (en) * 1954-05-17 1958-04-15 Gruenenthal Chemie Products of the amino-piperidine-2-6-dione series
DE1093364B (de) * 1956-06-11 1960-11-24 Gruenenthal Chemie Verfahren zur Herstellung von Derivaten von Amino-piperidin-2,6-dionen
US3081308A (en) * 1959-12-29 1963-03-12 Searle & Co 5-carbocyclic-3-imidomethyloxazolidines and process
US3314969A (en) * 1963-07-30 1967-04-18 Chevron Res Process for the preparation of n-polyhaloethylthio compounds
US3457272A (en) * 1964-03-03 1969-07-22 Wyeth John & Brother Ltd 4-(o-benzoylsulfimido)lower fatty amines
US3314953A (en) * 1964-03-16 1967-04-18 Richardson Merrell Inc 1-substituted-3-phthalimido-2, 5-dioxopyrrolidines
US3436396A (en) * 1967-04-19 1969-04-01 Mcneilab Inc 1,4 and 1,5-bis(gamma-hydroxy-gamma,gamma-di-(2-pyridylmethyl)) - 5 - norbornene - 2,3 - dicarboximide and derivatives thereof
US3453271A (en) * 1967-05-02 1969-07-01 Mcneilab Inc Di-substituted 5-norbornene 2,3-dicarboximides

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4132799A (en) * 1975-05-09 1979-01-02 Merck & Co., Inc. N-(Benzoxazolinyl-2-one)-tricyclic dicarboximides
US20020061923A1 (en) * 1993-03-01 2002-05-23 D'amato Robert Methods and compositions for inhibition of angiogenesis with EM-138
US7723361B2 (en) 1993-03-01 2010-05-25 Celgene Corporation Methods for inhibiting undesired angiogenesis in patients having tumors with thalidomide
USRE40360E1 (en) * 1993-03-01 2008-06-03 The Children's Medical Center Corporation Methods for inhibition of angiogenesis with a composition comprising 3-hydroxythalidomide
US5712291A (en) * 1993-03-01 1998-01-27 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US6071948A (en) * 1993-03-01 2000-06-06 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US6114355A (en) * 1993-03-01 2000-09-05 D'amato; Robert Methods and compositions for inhibition of angiogenesis
US8143283B1 (en) 1993-03-01 2012-03-27 The Children's Medical Center Corporation Methods for treating blood-born tumors with thalidomide
US6235756B1 (en) 1993-03-01 2001-05-22 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis by thalidomide
US6977268B2 (en) 1993-03-01 2005-12-20 Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis with EM-138
US6469045B1 (en) 1993-03-01 2002-10-22 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis with EM-138
US5593990A (en) * 1993-03-01 1997-01-14 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US20050215593A1 (en) * 1993-03-01 2005-09-29 D Amato Robert Methods treating tumors with thalidomide
US20070021464A1 (en) * 1993-03-01 2007-01-25 D Amato Robert Methods and compositions for inhibition of angiogenesis with EM-12 Derivatives
US8012996B2 (en) 1993-03-01 2011-09-06 Children's Medical Center Corporation Methods and composition for inhibition of angiogenesis
US6420414B1 (en) 1993-03-01 2002-07-16 The Children's Medical Center Corporation Amino derivatives of EM-138 and methods of treating angiogenesis with same
US20030176463A1 (en) * 1993-03-01 2003-09-18 D'amato Robert Methods and compositions for inhibition of angiogenesis with phthaloyl glutamic acid derivatives
EP1004580A3 (de) * 1993-07-02 2002-10-02 Celgene Corporation Imide als Inhibitoren von TNF alpha
RU2174516C2 (ru) * 1993-07-02 2001-10-10 Селген Корпорейшн Имиды как ингибиторы tnf-альфа
US5443824A (en) * 1994-03-14 1995-08-22 Piacquadio; Daniel J. Topical thalidomide compositions for surface or mucosal wounds, ulcerations, and lesions
US5605684A (en) * 1994-03-14 1997-02-25 Piacquadio; Daniel J. Topical thalidomide compositions for surface of mucosal wounds, ulcerations, and lesions
US7867975B2 (en) 1995-10-23 2011-01-11 The Children's Medical Center Corporation Therapeutic antiangiogenic endostatin compositions
US7495089B2 (en) 1995-10-23 2009-02-24 The Children's Medical Center Corporation Therapeutic antiangiogenic endostatin compositions
US20090036412A1 (en) * 1996-11-05 2009-02-05 D Amato Robert J Methods and Compositions for Inhibition of Angiogenesis
US20070049566A1 (en) * 1996-11-05 2007-03-01 D Amato Robert J Methods and Compositions for inhibition of angiogenesis
US7435745B2 (en) 1996-11-05 2008-10-14 Celgene Corporation Methods and compositions for inhibition of angiogenesis
US20030191098A1 (en) * 1996-11-05 2003-10-09 D'amato Robert J. Methods and compositions for inhibition of angiogenesis
US8039488B2 (en) 1996-11-05 2011-10-18 Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US6518298B2 (en) 1997-10-16 2003-02-11 Entremed, Inc. Methods and compositions for inhibition of angiogenesis with EM-138
US6228879B1 (en) 1997-10-16 2001-05-08 The Children's Medical Center Methods and compositions for inhibition of angiogenesis
US7112602B2 (en) 1998-05-11 2006-09-26 The Children's Medical Center Corporation Methods of treating undesired angiogenesis with 2-methyl-EM-138
US20040127545A1 (en) * 1998-05-11 2004-07-01 Childrens' Medical Corporation Analogs of 2-phthalimidinoglutaric acid
US6673828B1 (en) 1998-05-11 2004-01-06 Children's Medical Center Corporation Analogs of 2-Phthalimidinoglutaric acid
US7812169B2 (en) 2000-11-30 2010-10-12 The Children's Medical Center Corporation Method of synthesis of 4-amino-thalidomide enantiomers
US8153806B2 (en) 2000-11-30 2012-04-10 The Children's Medical Center Corporation Synthesis of 4-amino-thalidomide enantiomers
US20030164219A1 (en) * 2002-02-20 2003-09-04 Joerg Brahm Headliner/duct assembly and welding process therefor

Also Published As

Publication number Publication date
DE1695346B2 (de) 1974-06-27
DE1695346C3 (de) 1975-02-13
CH530991A (de) 1972-11-30
AT278739B (de) 1970-02-10
DE1695346A1 (de) 1972-04-06
FR1570452A (de) 1969-06-13
CH551426A (de) 1974-07-15
GB1182709A (en) 1970-03-04

Similar Documents

Publication Publication Date Title
US3625946A (en) 1,4 endomethylene cyclohexane-2,3 endo-cio di carboximido glutarimides
DE68929049T2 (de) 1,4-Diazepin-Derivate und deren pharmazeutische Verwendung
DE3300774A1 (de) Neue spirocyclische aminosaeuren, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung sowie neue spirocyclische aminosaeuren als zwischenprodukte und verfahren zu deren herstellung
EP0133530B1 (de) 1,6-Naphthyridinon-Derivate, Verfahren zu deren Herstellung und diese enthaltende Arzneimittel
US3586683A (en) 2,5(5) - di(tri)substituted - 10b-hydroxy-3,6 - dioxo-octahydro-oxazolo(3,2-a) pyrrolo(2,1-c)pyrazine derivatives of lysergic acid
HU203891B (en) Process for producing pyrrolidino-piperazine-dion derivatives and pharmaceutical compositions contianing them as active components
US3285931A (en) Preparation of substituted pyrrole derivatives
US3056796A (en) 2.8-diazaspiro(4.5)decane-1.3 diones
US3666762A (en) 2{40 {62 -ISOPROPYL-5{40 {60 -n-PROPYL-9,10-DIHYDRO-ERGOPEPTINES
US3256276A (en) Substituted spiroimides
JPH05503509A (ja) Ｎ―置換されたナフタルイミド、その製造および使用
US3850928A (en) Substituted 6-alkylamino-2-phenyl-5-pyrimidine carboxylic acids
Zilkha et al. Syntheses of Amide Derivatives of DL-β-Carboxy-γ-aminobutyric Acid
US3660322A (en) Benzene-ring-substituted tetrahydro-quinazolines
US3489747A (en) 1,3 - dihydro - 5 - phenyl - 2h - 1,4 - benzodiazepin - 2 - one - 3 - carbamic acid esters and methods for their preparation
Madhav et al. 2‐Amino‐4‐aryl‐6‐(ω‐carboxyalkyl)‐5H‐pyrrolo [3, 4‐d] pyrimidin‐7‐(6H) ones. Preparation via a one‐pot synthesis of 1‐(ω‐carboxyalkyl)‐4‐carbethoxy‐2, 3‐dioxopyrrolidines
US3257398A (en) Polycyclic acids, anhydrides, imides and amines
CA1300146C (en) 12b-substituted 1-hydroxymethyl-octahydroindolo¬2,3-a|- quinolizine derivatives, process for the preparation and pharmaceutical compositions containing them
US3772299A (en) P'-alkoxy-ergotamines
US3563992A (en) 1,4-diaza-bicyclo(4,3,0)nonane-2,5,9-triones
Dox et al. SPIRO-PYRIMIDINES. I. CYCLOBUTANE-1, 5-spiro-PYRIMIDINES.
US3423412A (en) Benzopyrroloquinazolinones
US3712889A (en) Oxodihydrobenzothiazine-s-dioxides
US3652634A (en) Process for preparing a ((2-benzoyl-phenylcarbamoyl)methyl)-hydroxy carbamic acid ethyl ester ethyl carbonate
US5098919A (en) Pyrrolo(2,1-b)thiazole derivatives